Reproduction in women depends upon the dynamic interaction of several compartments of the female reproductive system. The hypothalamic-pituitary unit orchestrates a series of events affecting the ovaries and the uterine-endometrial compartment which leads to the production of the ovum, ovulation, and ultimately appropriate conditions for fertilization. Specifically, hypothalamic hormones enhance the release of the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH). In the ovary, gonadotropins enhance the development of follicles which, in turn, secrete steroids (estradiol, progesterone) and peptides (inhibin, activin). Estradiol and inhibin levels progressively increase during the follicular phase of the menstrual cycle until ovulation. Afterwards, the follicular unit forms the corpus luteum which produces progesterone. Ovarian hormones, in turn, regulate the secretion of gonadotropins by establishing a classical long-loop negative feedback mechanism. The elucidation of these control mechanisms has provided opportunities for the development of effective strategies to control fertility, including both the enhancement of fertility and contraception. For recent reviews of FSH action see "FSH Action and Intraovarian Regulation", B. C. J. M. Fauser, editor, Parthenon Publishing Group, 1997 and Hsueh, A. J., Bicsak, T., Jia, X. -C., Dahl, K. D., Fauser, B. C. J. M., Galway, A. B., Czwkala, N., Pavlou, S., Pakoff, H., Keene, J., Boime, I, "Granulosa Cells as Hormone Targets: The role of Biologically Active Follicle-Stimulating Hormone in Reproduction" Rec. Prog. Horm. Res., 1989, 45, 209-277.
Current hormonal contraception methods are steroidal and take advantage of long-loop feedback inhibition of gonadotropin secretion, as well as effecting peripheral mechanisms such as sperm migration and fertilization. An alternative strategy for hormonal contraception would be the development of specific antagonists of the receptor for FSH. Such antagonists would disrupt the actions of FSH on follicular development, thus producing the desired contraceptive effect. The utility of this strategy is supported by mechanism of infertility of women with resistant ovary syndrome. The infertility experienced by these women is the result of non-functional FSH receptors (K. Aittomaki, J. L. D. Lucena, P. Pakarinen, P. Sistonen, J. Tapanainnen, J. Gromoll, R. Kaskikari, E. -M. Sankila, H. Lehvaslaiho, A. R. Engel, E. Nieschlag, I. Huhtaniemi, A. de la Chapelle "Mutation in the Follicle-Stimulating Hormone Receptor Gene Causes Hereditary Hypergonadotropic Ovarian Failure" Cell, 1995, 82, 959-968). This approach to contraception also appears applicable to men, since idiopathic male infertility seems related to a reduction in FSH binding sites. Moreover, men with selective FSH deficiency are oligo-or azoospermic with normal testosterone levels and present normal virilization. Therefore, orally active FSH antagonists may provide a versatile method of contraception.
Suramin Sodium, is an anticancer agent with a wide variety of activities. Recently suramin was shown to inhibit FSH binding to its receptor (Daugherty, R. L.; Cockett, A. T. K.; Schoen, S. R. and Sluss, P. M. "Suramin inhibits gonadotropon action in rat testis: implications for treatment of advanced prostate cancer" J. Urol. 1992, 147, 727-732). This activity causes, at least in part, the decrease in testosterone production seen in rats and humans that were administered suramin (Danesi, R.; La Rocca, R. V.; Cooper, M. R.; Ricciardi, M. P.; Pellegrini, A.; Soldani, P.; Kragel, P. J.; Paparelli, A.; Del Tacca, M.; Myers, C. E, "Clinical and experimental evidence of inhibition of testosterone production by suramin." J. Clin. Endocrinol. Metab. 1996, 81, 2238-2246). Suramin is the only non-peptidic small molecule that has been reported to be an FSH receptor binding antagonist. ##STR3##
Prior art compounds include those of J. Dannheim, U. Reiher and W. H. Russ (EP 630946) disclosed compounds (A) and (B) as reactive dyes. ##STR4##
C. Schumacher and W. H. Russ (EP 675172) disclosed compound (C) as a water soluble reactive dye. ##STR5##
K. Kunder and K. J. Herd (E( 652262) disclosed compound (D) as a reactive dye. ##STR6##
H. W. Russ, H. Tappe and C. Schumacher (EP 629667) disclosed compound (E) as a reactive dye. ##STR7##
U. Reither, J. Dannheim and W. H. Russ (EP 624630) disclosed compound (F) as a reactive dye. ##STR8##
J. Dannheim and W. H. Russ (EP 513657) disclosed compounds (G) and (H) as reactive dyes. ##STR9##
J. Szadowski and Z. Niewiadomski [Barwniki, Srodki Pomocnicze 1996, 40, 55-62] disclosed compounds (I) and (J) as dyes. ##STR10##
K. J. Herd, F. M. Stoehr and H. Hermann (EP 272532) disclosed compound (K) as a reactive dye. ##STR11##
H. Ischer and H. Siegrist (CH 463656) disclosed compound (L) as a reactive dye. ##STR12##
P. Grandjean (FR 1517223) discolosed compound (M) as a reactive dye. ##STR13##
Compound (N) (CAS registry no 67990-25-4) was disclosed. ##STR14##
L. Ruggli (Helv. Chim. Acta 1939, 22, 1170-1177 disclosed the compounds of formula (O) and (P). ##STR15##
These prior art compounds do not possess the substitutions on the triazene or benzoyl rings seen in the present compounds of formula (I).